1. Field of the Invention
The present invention relates to a process for the preparation of hydroxyethyl starch for use as a plasma expander.
2. Discussion of the Prior Art
W. Ziese, Z. Physiol. Chem. 229, 213 (1934); 235, 235 (1935), synthesized already 1934 hydroxyethyl starches (HES) and tested them as substrates for amylases of different origin. Husemann and Resz, Journal of Polym. Science 19, 389 (1959), synthesized HES as model substance for amylose so as to study fermentative degradation and to discover possible degradation in different reactions. Processes for preparing HES for industrial purposes have been known even longer and have been disclosed in many patent specifications. The use of HES for medical purposes as a plasma substitute in animals was described for the first time by Wiedersheim, Arch. Int. Pharmacodyn. Therap. 111, 353-61 (1957).
Wiedersheim prepared HES using the known process of hydroxyethylation of starch in alkaline-aqueous medium by means of ethylene oxide. However, he used corn starch hydrolytically degraded to lower molecular weights as the hydroxyethylation substrate so as to obtain HES suitable as a plasma substitute. In succession, numerous works and patents were published concerning the preparation of HES for human therapy.
As already mentioned, up to now, the hydroxyethyl starch which has been used in recent time as a plasma expander has been prepared by alkaline hydroxyethylation of starch. The reaction mixture which is obtained thereby is strongly alkaline and must be neutralized before it can be further worked up. The neutralization step produces a relatively large amount of salt, typically sodium chloride, in the reaction mixture. Dialysis methods have been proposed for removing the salt. However, such methods are extremely expensive with respect to time, apparatus and energy, and involve, furthermore, the danger of contaminating the reaction mixture. Therefore, many attempts have been made to replace this complicated process by a simpler working up process. Thus, it has been proposed, for example, to carry out the neutralization of the reaction solution with cation exchang resins. It is true that such a process is simpler with respect to the apparatus; however, that process does not prevent the danger of biological contamination (infection) of the preparation due to the great surface area of the exchange resin particles being readily populated with bacteria and fungi.
Summarizing, according to the previously known processes, it is only with extreme difficulty that hydroxyethyl starch can be prepared having the necessary purity and sterility to be used as a plasma substitute.